A few years ago targeted echocardiography (or functional echo) became all the rage. As trainees in this field have become spread across this country and others it is natural that attention would turn to other deficiencies in Neonatology. The new thing on the block appears to be Neonatal Neurocritical Care with the concept being that building teams devoted to the pursuit of better neuro outcomes for babies is needed. I am not here to say otherwise but to acknowledge that this is a good thing for our field. Building a local expertise for such at risk infants is a wise plan as with anything if we focus and a small area and put lots of hours in you can only get better.
New CPS Statement
This past month the CPS released a new position statement entitled Neuroprotection from acute brain injury in preterm infants . As Chair of the committee and writer of this blog I thought it might be nice to point out the timely release of this statement. One of the authors Dr. Khorshid Mohammad was recently in Winnipeg for our POCUS workshop and spoke about neurocritical care for neonates as part of the meeting. I would encourage you to read through the new statement but wanted to point out a couple interesting recommendations that serve as a departure from practice (or at least my own).
Antenatal steroids should be given to those 34 0 – 34 6/7 weeks.
This is something that comes out of the literature that has looked more broadly at the group from 34 0/7 – 36 6/7 weeks. The recommendation really is an acknowledgement that if there is benefit it is likely coming from those infants just past the 34 week mark. Older infants may benefit but the numbers needed to treat are so high that it calls into question the real need for such treatment.
A new approach to treating hypotension
An approach that moves away from treating numbers is recommended. How many times have you been asked how low a blood pressure should be allowed to drift before starting inotropes? Evidence is mounting that early use of inotropes themselves is linked to IVH. A more nihilistic approach is favoured here by looking at measures of end organ impact before instituting such therapy. What is the urine output, perfusion and lactate should motivate treatment more than just the number itself. If you are fortunate enough to have targeted echocardiography at the ready it is recommended to utilize that modality to help guide your treatment as well.
I won’t go through the whole document as I would love for you to read it yourself and see how it may apply to your own centre. I think the statement is significant though in that it really does marshal in a new era in the field of neuroprotection. I am pleased that the CPS is taking a position on this and if you need any other guidance be sure to visit our webpage at the Fetus and Newborn Committee which can be found at:
To be sure there are fans of both HFNC and CPAP out there. I have often heard from other Neonatologists that they use HFNC and find positive results while other centres refuse to use it in favour of the tried and true CPAP. Turning to the literature you will find some conflicting results with some studies suggesting equity and others more recently favouring CPAP. There has been speculation as to why one would be superior to the other and now we appear to have some answers as to where the differences lie.
A Physiologic Study
Liew et al published Physiological effects of high-flow nasal cannula therapy in preterm infants this month in an elegant study of 40 infants. The study was fairly simple in design either randomizing infants <37 weeks to starting with nCPAP +6 and then transitioning to 8 l/min HFNC followed by stepwise reductions of 1 l/min until 2 l/min was reached or the reverse, starting with 2 l/min and working their way up and then transitioning to nCPAP+6. All infants were on one or the other modality at the start and were all at least 3 days old, they were randomized to one or the other arm regardless of where they started off. Physiologic measurements were taken at each step including the following:
Mv -Minute ventilation
pEEP – nasopharyngeal end-expiratory pressure
pEECO2 -nasopharyngeal end-expiratory CO2
RR – respiratory rate;
SpO2 – oxygen saturation
TCCO2 – transcutaneous CO2
Vt – tidal volume
A Fabian device was used to deliver either HFNC or CPAP at the different flows for all patients.
The authors certainly found some interesting results that I think shed some light on why comparisons of HFNC and CPAP have been so inconsistent.
Table 2 contains the results of the study and I will point out the main findings below.
1. Flow matters – Compared to nCPAP+6 which is fairly consistent flows below 6 l/min deliver pEEP that is below 6 cm H2O.
2. Keep the mouth shut – With CPAP whether the mouth is open or closed the Fabian device delivers +6 cm H2O. As you can see from the table, when the mouth is open transmitted pressures drop off substantially. The infant put on a flow of even 6-8 l/min of HFNC sees pressures less than +6 consistently.
3. As flows increase end expiratory CO2 decreases. HFNC seems to help wash out CO2
4. Low flow rates on HFNC do not seem to help with ventilation as much as higher flow rates. In order to maintain Mv these infants at 2 l/min flow become tachypneic. The low pressures produced likely cause some atelectasis and hence tachypnea.
Size matters! Beware of excessive pressures.
An additional finding of this study was that on “multiple linear regression, flow rate, mouth position, current weight and gestation but not prong-to-nares ratio significantly predicted pEEP and account for a significant amount of its variance (F(4431)=143.768, p<0.0001), R2=0.572, R2=adjusted 0.568).” Essentially, infants under 1000g in particular could see pEEP levels as high as 13 cm H2O with flows of 8 l/min. The variability in transmitted pressures with HFNC is shown nicely in this figure from the study.
As flows increase above 6 l/min the actual pressures delivered become less reliable.
Looking at this data, it becomes evident why HFNC may be failing in its attempt to dethrone nCPAP. In order to achieve higher pressures and provide comparable distending pressure to nCPAP you need higher flows. With higher flows though come the problem of greater variability in delivered pressure. While the average pressure delivered may be equivalent or even higher than a CPAP of +6, in some infants (especially those below 1000g) one may be delivering significantly higher pressures than intended which may help with oxygenation and preventing intubation but others may be seeing far less than needed.
What it comes down to is that nCPAP is better at delivering a consistent amount of pressure. Studies using lower flows of HFNC likely failed to show superiority to CPAP as they just didn’t deliver enough pressure. An example of this was the study by Roberts CT et al Nasal High-Flow Therapy for Primary Respiratory Support in Preterm Infants, in which flows of 6-8 l/min were used. Other studies using higher pressures could have been problematic due to open mouths, or larger babies not receiving as much benefit.
I am not saying that we should throw out HFNC entirely however. Depending on the unit you practice in you might not be able to use CPAP but HFNC may be allowed. If you had to choose between no support or HFNC I would likely go with the HFNC. For me at least, if I want to delivery reliable pressures in my tertiary care NICU I will be calling for the CPAP.
I have written about non-traditional methods of providing surfactant to newborns previously. The practice of intubating a preterm infant to administer surfactant and leaving the endotracheal tube in with a slow wean of ventilation is mostly a thing of the past (at least in my units). Strategies have evolved and have seen the development of the INSURE technique, LISA methods, use of an LMA to delivery surfactant and even simple deposition into the pharynx all with variable success.
Poractant alfa at 200 mg/kg was used in this study and delivered via aerosolization using a vibrating membrane called the eFlow. The authors chose to look at infants from 29 0/7 to 33 6/7 weeks at birth and stratified them into two groups of 29 0/7 to 31 6/7 and 32 0/7 to 33 6/7 weeks. They estimated a need for 70 babies based on an anticipated failure rate of 30% in the control group vs 5% in the treatment group. Unfortunately, due to several reasons the study was only able to recruit 64 babies for randomization before being stopped due to the recruitment issues. The design of the study included adequate blinding with a sham procedure and there were predefined “failure criteria” necessitating intubation at the outset of the study. These criteria are acceptable to me as they are similar enough to my own practice and were:
1. FiO2 >0.35 over more than 30 min OR FiO2 >0.45 at
2. More than four apnoeas/hour OR two apnoeas requiring bag
and mask ventilation.
3. Two capillary blood gas samples with a pH <7.2 and partial pressure of carbon dioxide >65 mm Hg (or partial pressure
of carbon dioxide in arterial blood (PaCO2) >60 mm Hg if
arterial blood gas sample).
4. Intubation deemed necessary by the attending physician.
What did they find?
The primary outcome CPAP failure within 72 hours of birth was indeed different in the two groups.
CPAP failure by 72 hours
CPAP + surfactant
(RR (95% CI)=0.526 (0.292 to 0.950))
Clearly the event rates were quite off from what they expected in the power calculation but given that they found a difference as opposed to no difference at all the fact that they didn’t recruit the numbers they planned is of less importance.
However, what is interesting is when they looked at the planned analysis by stratification an interesting finding emerged.
Group 1 (29 0/7 to 31 6/7)
CPAP failure by 72 hours
CPAP + surfactant
(RR (95% CI)=0.860 (0.389 to 1.90))
Group 2 (32 0/7 to 33 6/7
CPAP failure by 72 hours
CPAP + surfactant
(RR (95% CI)=0.254 (0.089 to 0.727))
There were a number of secondary outcomes looked at as well which may be of interest to you but as the numbers here are quite small I will not comment other than to say there was no increased incidence of complications with surfactant administration in this fashion. Also for those who ultimately failed CPAP the time when they did so was quite delayed compared to CPAP alone. Age at intubation for nCPAP failure, hours 4.9 (2.7–10.6) 11.6 (9.0–31.1) 0.008*
What can we take from this?
I believe these results are encouraging even if the study is a small one. The message I take from this study is that aerosolization of surfactant delivers some amount of product to the lungs. Those with more significant RDS or smaller lungs (those in the 29 0/7 to 31 6/7 group) may not get enough surfactant to treat their RDS sufficiently to avoid intubation. Those with less significant RDS or a larger number of alveoli get “enough” of a dose delivered to the alveoli to make a difference and avoid intubation. It is worth stressing that there can be no specific comment about using this strategy in even more immature infants as they weren’t tested. If I had to guess though, I would expect no difference given the findings in the smaller group.
As a physician responsible for transport though I am interested in the potential benefits to those born in non-tertiary centres. Many centres lack individuals with the confidence and skill to regularly place endotracheal tubes. For these centres it may be that providing nebulized surfactant could delay the time to treatment failure, allowing more time for a trained transport team to arrive. Training of course would be needed in these centres on how to administer surfactant in this way but it is an interesting concept to consider. With a near tripling of the average time to treatment failure the extra hours on CPAP would be much appreciated when weather delays or difficulty securing air assets means long delays in transport team arrivals.
To be sure this isn’t the last study of this kind but it certainly is an interesting start and one that will no doubt produce questions that will help formulate the next study design.